GRAFTS OF EGF-RESPONSIVE NEURAL STEM-CELLS DERIVED FROM GFAP-HNGF TRANSGENIC MICE - TROPHIC AND TROPIC EFFECTS IN A RODENT MODEL OF HUNTINGTONS-DISEASE

The present study examined whether implants of epidermal growth factor (EGF)-responsive stems cells derived from transgenic mice in which th e glial fibrillary acid protein (GFAP) promoter directs the expression of human nerve growth factor (hNGF) could prevent the degeneration of striatal neurons in a rodent model of Huntington's disease (HD). Rats received intrastriatal transplants of GFAP-hNGF stem cells or control stem cells followed 9 days later by an intrastriatal injection of qui nolinic acid (QA). Nissl stains revealed large striatal lesions in rat s receiving control grafts, which, on average, encompassed 12.78 mm(3) . The size of the lesion was significantly reduced (1.92 mm(3)) in rat s receiving lesions and GFAP-hNGF transplants. Rats receiving QA. lesi ons and GFAP-hNGF-secreting grafts stem cell grafts displayed a sparin g of striatal neurons immunoreactive (ir) for glutamic acid decarboxyl ase, choline acetyltransferase, and neurons histochemically positive f or nicotinamide adenosine diphosphate. Intrastriatal GFAP-hNGF-secreti ng implants also induced a robust sprouting of cholinergic fibers from subjacent basal forebrain neurons. The lesioned striatum in control-g rafted animals displayed numerous p75 neurotrophin-ir (p75(NTR)) astro cytes, which enveloped host vasculature. In rats receiving GFAP-hNGF-s ecreting stem cell grafts, the astroglial staining pattern was absent. By using a mouse-specific probe, stem cells were identified in all an imals. These data indicate that cellular delivery of hNGF by genetic m odification of stem cells can prevent the degeneration of vulnerable s triatal neural populations, including those destined to die in a roden t model of HD, and supports the emerging concept that this technology may be a valuable therapeutic strategy for patients suffering from thi s disease. (C) 1997 Wiley-Liss, Inc.